Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular ...coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.
The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic ...activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.
It is well established that spermatogenesis is controlled by gonadotrophins and testosterone. However, a role for estrogens in male reproduction recently was suggested in adult mice deficient in ...estrogen receptor α . These mice became infertile primarily because of an interruption of fluid reabsorption by the efferent ductules of the epididymis, thus leading to a disruption of the seminiferous epithelium Hess, R. A., Bunick, D., Lee, K. H., Bahr, J., Taylor, J. A., Korach, K. S., and Lubahn, D. B. (1997) Nature (London) 390, 509-512. Despite the demonstration of the aromatase enzyme, which converts androgens to estrogens, and estrogen receptors within the rodent seminiferous epithelium, the role of aromatase and estrogen in germ cell development is unknown. We have investigated spermatogenesis in mice that lack aromatase because of the targeted disruption of the cyp19 gene (ArKO). Male mice deficient in aromatase were initially fertile but developed progressive infertility, until their ability to sire pups was severely impaired. The mice deficient in aromatase developed disruptions to spermatogenesis between 4.5 months and 1 year, despite no decreases in gonadotrophins or androgens. Spermatogenesis primarily was arrested at early spermiogenic stages, as characterized by an increase in apoptosis and the appearance of multinucleated cells, and there was a significant reduction in round and elongated spermatids, but no changes in Sertoli cells and earlier germ cells. In addition, Leydig cell hyperplasia/hypertrophy was evident, presumably as a consequence of increased circulating luteinizing hormone. Our findings indicate that local expression of aromatase is essential for spermatogenesis and provide evidence for a direct action of estrogen on male germ cell development and thus fertility.
In the South West Pacific region, the striking geographical correlation between the frequency of α+-thalassemia and the endemicity of Plasmodium falciparum suggests that this hemoglobinopathy ...provides a selective advantage against malaria. In Vanuatu, paradoxically, α+-thalassemia increases the incidence of contracting mild malaria in the first 2 years of life, but severe disease was too uncommon to assess adequately. Therefore, we undertook a prospective case-control study of children with severe malaria on the north coast of Papua New Guinea, where malaria transmission is intense and α+-thalassemia affects more than 90% of the population. Compared with normal children, the risk of having severe malaria was 0.40 (95% confidence interval 0.22-0.74) in α+-thalassemia homozygotes and 0.66 (0.37-1.20) in heterozygotes. Unexpectedly, the risk of hospital admission with infections other than malaria also was reduced to a similar degree in homozygous (0.36; 95% confidence interval 0.22-0.60) and heterozygous (0.63; 0.38-1.07) children. This clinical study demonstrates that a malaria resistance gene protects against disease caused by infections other than malaria. The mechanism of the remarkable protective effect of α+-thalassemia against severe childhood disease remains unclear but must encompass the clear interaction between this hemoglobinopathy and both malarial and nonmalarial infections.
The removal of radioactivity from liquid scintillator has been studied in preparation of a low background phase of KamLAND. This paper describes the methods and techniques developed to measure and ...efficiently extract radon decay products from liquid scintillator. We report the radio isotope reduction factors obtained when applying various extraction methods. During this study, distillation was identified as the most efficient method for removing radon-born lead from liquid scintillator.
Corticosteroids have been used successfully to prolong the duration of local anesthetic action after peripheral nerve and epidural blockade. We hypothesized that the addition of dexamethasone to ...mepivacaine would prolong the duration of analgesia after ultrasound-guided supraclavicular brachial plexus block for patients undergoing upper-limb surgery.
After Federal Health Department and institutional review board approval, 45 adult patients undergoing elective hand or forearm surgery under supraclavicular brachial plexus blockade were randomized to receive either 30 mL mepivacaine 1.5% plus dexamethasone 8 mg (4 mg/mL), or 30 mL mepivacaine 1.5% plus 2 mL normal saline. The primary outcome measure was duration of analgesia. Secondary outcomes included onset times of sensory and motor blockade, pain and satisfaction scores, analgesic consumption, and block-related complications.
Patient characteristics were similar between groups. The median duration of analgesia was significantly prolonged in the Dexamethasone group (332 mins; interquartile range, 225-448 mins) compared with the Normal Saline group (228 mins; interquartile range, 207-263 mins; P = 0.008). The onset times of sensory and motor block were similar between the groups. Complications were minor and transient and did not differ between groups at 2 weeks postoperatively.
The addition of dexamethasone to mepivacaine prolongs the duration of analgesia but does not reduce the onset of sensory and motor blockade after ultrasound-guided supraclavicular block compared with mepivacaine alone.
The mismatch negativity, a negative component in the auditory event-related potential, is thought to index automatic processes involved in sensory or echoic memory. The authors' goal in this study ...was to examine the topography of auditory mismatch negativity in schizophrenia with a high-density, 64-channel recording montage.
Mismatch negativity topography was evaluated in 23 right-handed male patients with schizophrenia who were receiving medication and in 23 nonschizophrenic comparison subjects who were matched in age, handedness, and parental socioeconomic status. The Positive and Negative Syndrome Scale was used to measure psychiatric symptoms.
Mismatch negativity amplitude was reduced in the patients with schizophrenia. They showed a greater left-less-than-right asymmetry than comparison subjects at homotopic electrode pairs near the parietotemporal junction. There were correlations between mismatch negativity amplitude and hallucinations at left frontal electrodes and between mismatch negativity amplitude and passive-apathetic social withdrawal at left and right frontal electrodes.
Mismatch negativity was reduced in schizophrenia, especially in the left hemisphere. This finding is consistent with abnormalities of primary or adjacent auditory cortex involved in auditory sensory or echoic memory.
Landsat-5 has been imaging the Earth since March 1984, and Landsat-7 was added to the series of Landsat instruments in April 1999. The Landsat Project Science Office and the Landsat-7 Image ...Assessment System have been monitoring the on-board calibration of Landsat-7 since launch. Additionally, two separate university teams have been evaluating the on-board thermal calibration of Landsat-7 through ground-based measurements since launch. Although not monitored as closely over its lifetime, a new effort is currently being made to validate the calibration of Landsat-5. Two university teams are beginning to collect ground truth under Landsat-5, along with using other vicarious calibration methods to go back into the archive to validate the history of the calibration of Landsat-5. This paper considers the calibration efforts for the thermal band, band 6, of both the Landsat-5 and Landsat-7 instruments. Though stable since launch, Landsat-7 had an initial calibration error of about 3 K, and changes were made to correct for this beginning 1 October 2000 for data processed with the National Landsat Archive Production System (NLAPS) and beginning 20 December 2000 for data processed with the Landsat Product Generation System (LPGS). Recent results from Landsat-5 vicarious calibration efforts show an offset of -0.7 K over the lifetime of the instrument. This suggests that historical calibration efforts may have been detecting errors in processing systems rather than changes in the instrument. A correction to the Landsat-5 processing has not yet been implemented but will be in the near future.
This paper examines performance evaluation outcomes for middle managers in the garment sector in Sri Lanka and seeks to explain variations in levels of job involvement and perceptions of ...organizational support. Some 155 middle managers across three firms were segregated into high- and low-performing groups. High-performing managers tended to have higher perceptions of organizational support, resulting in a social exchange relationship with their employer, and expressed higher job satisfaction and lower turnover intentions. Managers assessed as low performers experienced more negative perceptions of organizational support, lower job satisfaction and an economic exchange relationship with their employer. Significantly, for both high and low performers these outcomes were moderated by job involvement. These findings highlight the need for organizations to pay careful attention to the factors influencing job involvement and perceived organizational support. The paper concludes with a discussion on the practical implications of the findings for human resource managers.
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